SUMMARY:
Recent evidence suggests a link between cardiovascular and neurodegenerative disease. Interestingly there are common, yet independent, risk factors associated with them. The so-called epidemics of the 21st century do not only take millions of lives yearly, but also carry tremendous socio-economic burden for patients, their families and the society as a whole.
Micro-hemorrhages and amyloid plaque deposition co-localize in the cortex. The cause of cerebral micro-bleeds remains unresolved, though associations have been made with aortic stiffness, increased pulse wave velocity, and aging. Indeed, changes in pulsatile shear stress provoked by arterial stiffening inherent to the aging process, or indirect flow effects on the immunological system, extend to the brain, an organ with low peripheral resistance.
How alterations in the microvascular flow affect the functional and phenotypical aspects of endothelial cell state within the blood-brain barrier (BBB) remains elusive. We hypothesize that human brain microvascular endothelial cell (EC) state changes with the flow environment, and that such cellular state plays a significant role in brain disease progression. That is, EC in one state may exacerbate toxicity and in another mute it. In other words, changes in microvascular EC state might increase toxicity evidenced by micro-hemorrhages and amyloid plaque deposition co-localized in the cortex.
To prove our hypothesis, we aim to:
1) Examine the impact of flow waveform parameters on the brain microvasculature. We will look for toxic effects over time utilizing both in vitro co-cultures of EC and astrocytes in a bioreactor, and animal models to track changes in the BBB.
2) Determine whether toxicity is provoked by increased transport of solutes into the extra-luminal space, by alterations in the proteins secreted by EC, or by both.
3) Study which aspects of flow can be modulated in such a way to reduce or increase (optimize) BBB performance.
Potential benefits derived from this study include:
- Gaining a better understanding of the role of EC and flow in cerebrovascular disease and BBB pathophysiology.
- Help designing agents that can prevent or delay BBB malfunction.
- Develop new mathematical predictive models of biological systems to elucidate potential diagnostic tools and targets for cerebrovascular disease treatment.
- Overall ameliorate life quality of elderly diseased patients; our multidisciplinary translational approach is embedded in a culture of close collaboration with industrial partners that ensure technology transfer of research results from bench to bed site.
- Further international research networks, which will serve as basis for future EU/USA grant applications.
The research team provides unique critical mass to achieve the proposed goals. IQS researchers will couple the skills related to bioengineering, chemical engineering,material science and applied mathematics to incorporate computer-aided design modeling and design scaffolds to build physiologically relevant in vitro models. Neurologist at Hospital del Mar are experts in diagnosis, current treatments, and specimen analysis of cerebrovascular disease. Prof. Edelman’s lab at MIT and Prof. O’Rourke’s lab in Sydney will advise with regards to cardiovascular disease, vascular biology, and preclinical models. Benefiting from her double appointment as IQS professor and MIT scientist, Dr. Balcells will integrate the combined effort of the committed multidisciplinar team.

IQS work:
Work at IQS focuses on flow simulations of arteries,
and damping of wave that propagates to reach BBB:
• Testing and simulations focus on the flow pressures and velocities to damp arterial pressure wave. First material is tested to determine the hysteresis and energy absorption.

Damping and hysteresis simulation with ESI software PAMCRASH. Validation model to feed coupled fluid-structure interaction simulations.
All process simulated with Pamcrash. First the tube is flattened and then loaded in cycles of tension and compression.

With help from ESI simulations are carried out to understand pulse from a basic peristaltic pump using SPH formulation for the liquid.

Combination of several cardiac pulses are under examination to achieve simulation stability.
• Prototypes are manufactured using several techniques. CAD is integrated to generate simulations, CNC of moulds and STL files for 3D printing.